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Bioanalytical development for application in therapeutic drug monitoring: focus on drugs used in psychiatry
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Introduction: Since the 1950s and onwards, many new psychoactive drugs have been successfully introduced in clinical practice. A common feature of these drugs is a profound metabolism before clearance from the body. Genetic and phenotypic factors among patients can be anticipated to interact with the metabolism and therefore a major variance in the drug concentration between patients upon the same dose may be found. In later years there has been an increasing awareness, that the individual drug metabolism and drug body disposition do not only refer to the parent compound and major metabolites but also to the separate enantiomers in the case of chiral drugs.

Bioanalytical methods for determination of drug concentrations have constantly been developed to assess the large pharmacokinetic variability of these drugs. Moreover, in the psychopharmacological practice these methods are often extended into a "Therapeutic Drug Monitoring (TDM) Service". A TDM service is used to determine the patient-specific drug analytical outcome in order to assess the precision in dose prescription as well as to recommend adequate dose adjustments for a particular patient.

Aim: The aim was to develop bioanalytical methods, utilising high performance liquid chromatography, for serum determinations in patients under chronic dosing schedules for some recently introduced drugs used in psychiatry.

Firstly, for the antidepressant drug reboxetine by an achiral methodology (paper I) consecutively extended to an enantioselective methodology for the individual enantiomers of the drug (paper II and III). Thereafter, after the evaluation of on-line extraction as an automated alternative to manually performed solid phase extraction for sample preparation (paper IV), apply on-line extraction in combination with ion-trap mass spectrometry detection for serum determination of the novel antipsychotic drug ziprasidone (paper V).

Results and Conclusion: The methodology described in paper I has been applied on more than 500 patient samples from the naturalistic clinical practice as well as from controlled clinical trials. The methodology has proven robust and reliable and, although manually performed, easy to handle. The kinetic outcome display a great variability in concentration outcome even within the same prescribed dose, i.e. through level samples in steady-state were found to be 660±400 nM on 8 mg/day.

Paper II, which describes the development of three approaches for direct chiral separation of reboxetine and O-deethylreboxetine enantiomers in the reversed phase mode, is in itself new and important. It is however, after applying MS2 detection, in paper III that the methodology is extended to include patients, i.e. patients from two separate clinical trials. Trial I comprised 23 patients on monotherapy with reboxetine and trial II comprised 47 patient from a naturalistic clinical setting. The pharrnacokinetic outcome displayed a S,S- over R,R-reboxetine ratio of about 0.5 with a rather pronounced inter-individual ratio (i.e. 0.2 to 0.9). The enantiomeric ratio did not correlate to the overall reboxetine concentration and the enantiomeric ratio was about 30% higher in females than in males. Repeated samples were analysed for trial I patients displaying an inter-individual coefficient of variation (CV) of about 17% meanwhile the intra-individual CV was about 4%. Calculating the noradrenaline reuptake inhibition (NARI) -activity out of the individual enantiomeric ratios showed that females may have a higher NARI-activity than males at a given reboxetine concentration.

Paper IV proves that online extraction offers a robust, reliable and, for the analyst, time saving alternative (above 80%) to manually performed off-line solid phase extraction for sample preparation (citalopram and its demethylated metabolites were used as model substances).

Paper V describes the development of a TDM process for ziprasidone and its S-methylated metabolite. The sample handling as well as the analytical process was subjected to a solid and satisfactory validation. It was proved that the lack of selectivity during on-line extraction can be compensated for by a selective form of detection, i.e. mass spectrometric detection.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2003. , 66 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 775
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-24800Local ID: 7064ISBN: 91-7373-534-5 (print)OAI: oai:DiVA.org:liu-24800DiVA: diva2:245123
Public defence
2003-02-28, Berzeliussalen, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-15Bibliographically approved
List of papers
1. Bioanalysis of racemic reboxetine and its desethylated metabolite in a therapeutic drug monitoring setting using solid phase extraction and HPLC
Open this publication in new window or tab >>Bioanalysis of racemic reboxetine and its desethylated metabolite in a therapeutic drug monitoring setting using solid phase extraction and HPLC
2001 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 23, no 1, 27-34 p.Article in journal (Refereed) Published
Abstract [en]

Reboxetine isa new antidepressant drug acting as a potent and selective noradrenaline reuptake inhibitor on the noradrenergic neuronal system. Because of an expected interindividual variability in drug metabolism in the clinical practice the need for therapeutic drug monitoring routines in psychiatry is always a prominent feature. In this application, the preferred bioanalytic methodology was solid phase extraction combined with reversed-Phase high-Performance liquid chromatography and ultraviolet detection at 210 nm. The technique proved reliable, with interday and intraday variation of less than 5% and a quantification limit for reboxetine and one of its main metabolites O-Desethylreboxetine (O-Reboxetine) at 5 and 30 nmol/L, respectively. The method was applied on serum samples from 38 patients treated chronically with reboxetine. These samples were drawn as trough levels in steady state with a dosage range of 2-16 mg/day. They evidenced a mean reboxetine concentration that was fairly linear and dose proportional, although the variance in concentration was large between patients, even those taking the same dosage. O-Reboxetine was detected in quantifiable amounts in only 1 of the 38 patients (<3%). In conclusion, these results suggest that a routine reboxetine therapeutic drug monitoring service that is robust enough to produce reliable and reproducible results may be introduced into everyday clinical practice.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27057 (URN)10.1097/00007691-200102000-00006 (DOI)11206039 (PubMedID)11703 (Local ID)11703 (Archive number)11703 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
2. Simultaneous determination of reboxetine and O-desethylreboxetine enantiomers using enantioselective reversed-phase high-performance liquid chromatography
Open this publication in new window or tab >>Simultaneous determination of reboxetine and O-desethylreboxetine enantiomers using enantioselective reversed-phase high-performance liquid chromatography
2002 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 947, no 2, 247-254 p.Article in journal (Refereed) Published
Abstract [en]

Current knowledge of stereoselective pharmacokinetics and different potencies of drug enantiomers requires the performance of stereoselective analysis during therapeutic drug monitoring in clinical practice. However, in the case of the new antidepressant drug reboxetine, no effort has been made so far to find a such a suitable system. Therefore, as a step towards developing an enantioselective bioanalytical method for reboxetine and the O-desethylreboxetine metabolite, three stereoselective chromatographic approaches have been investigated. Several chiral columns were tested, among them Chiral-AGP, ChiraGrom 2 and Chiral-CBH, which were able to simultaneously separate the two compounds into enantiomers in total running times of 28, 18 and 12 min, respectively.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27058 (URN)10.1016/S0021-9673(02)00012-2 (DOI)11704 (Local ID)11704 (Archive number)11704 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
3. Determination of serum reboxetine enantiomers in patients on chronic medication with racemic reboxetine
Open this publication in new window or tab >>Determination of serum reboxetine enantiomers in patients on chronic medication with racemic reboxetine
2003 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 25, no 2, 174-182 p.Article in journal (Refereed) Published
Abstract [en]

The chiral compound reboxetine is used as a selective noradrenaline re-uptake inhibitor (NARI) for the treatment of major depressive disorders. The pharmacokinetic variability of the enantiomers of the drug (S,S- and R,R-reboxetine) was studied using stereoselective high-performance liquid chromatography with mass spectrometric detection in a controlled clinical monotherapy situation (trial I) and a naturalistic clinical setting (trial II). Trial I included patients receiving racemic reboxetine as 6-month monotherapy for treatment of major depressive disorder. Trough level serum samples in steady state were analyzed for the concentration of the reboxetine enantiomers in study weeks 4, 12, and 24. In a therapeutic drug monitoring setting (trial II), 47 patients on doses ranging from 4 to 16 mg daily, including much polypharmacy, trough level steady-state serum samples were analyzed by the same bioanalytical method. Data from trials I and II were assessed to determine the inter- and intraindividual pharmacokinetic outcomes. The results showed that the median S,S/R,R ratio in steady state was 0.5 and ranged from 0.22 to 0.88. It was also shown that women have an approximately 30% higher S,S/R,R ratio than men. The S,S/R,R ratios of reboxetine were not found to correlate with reboxetine concentrations. To investigate the NARI activity of a circulating serum reboxetine concentration, a recalculation of the determined enantiomeric concentrations to previously demonstrated experimental NARI potencies of the drug enantiomers was performed. This partly novel concept of estimating pharmacodynamic activity showed that the serum NARI activity in women tended to be higher than in men at a given reboxetine concentration. In conclusion, the variability in the NARI activity per nmol/L reboxetine and the variability in the concentration outcome of the reboxetine enantiomers may justify the use of enantioselective drug monitoring in the clinic. The gender aspects of the drug have to be further assessed.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26798 (URN)10.1097/00007691-200304000-00006 (DOI)11406 (Local ID)11406 (Archive number)11406 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
4. On-line extraction using an alkyl-diol silica precolumn for racemic citalopram and its metabolites in plasma: results compared with solid-phase extraction methodology
Open this publication in new window or tab >>On-line extraction using an alkyl-diol silica precolumn for racemic citalopram and its metabolites in plasma: results compared with solid-phase extraction methodology
2001 (English)In: Journal of Chromatography B: Biomedical Sciences and Applications, ISSN 1387-2273, E-ISSN 1878-5603, Vol. 753, no 2, 365-373 p.Article in journal (Refereed) Published
Abstract [en]

Sample preparation is usually the most critical and time consuming step when using HPLC for drug analysis in biological matrixes. Sample extracts have to be clean considering both chromatographic interferences and column maintenance. To meet some of these criteria a fully automated on-line extraction (OLE) analysis method was developed for the antidepressant drug citalopram and its two demethylated metabolites, using an RP-C4-ADS extraction column. A comparison between the new OLE method and an off-line solid-phase extraction method showed that the two methodologies were equal in analytical precision but that the OLE method was faster and therefore superior in sample capacity per day.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26834 (URN)10.1016/S0378-4347(00)00579-X (DOI)11449 (Local ID)11449 (Archive number)11449 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
5. Biolanalysis of ziprasidone and its S-methylated metabolite in serum using on-line extraction and liquid chromatography-masspectrometry
Open this publication in new window or tab >>Biolanalysis of ziprasidone and its S-methylated metabolite in serum using on-line extraction and liquid chromatography-masspectrometry
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The novel antipsychotic agent Ziprasidone, (Zip) was introduced for clinical prescription in Sweden in the early spring of 2001. As of yet, no bioanalytical procedure suitable for a Therapeutic Drug Monitoring (TDM)-service of the drug has been presented. Therefore a bioanalytical methodology utilising online extraction on RP-C4-ADS columns combined with ion-trap masspectrometric detection for determination of Zip and its S-methylated metabolite (Smd-Zip) was developed. The stability of the analytes in serum was determined for establishing a correct sample handling procedure.

The calibration model for Zip and Smd-Zip had a linear response function in the concentration range 20 to 500 and 15 to 300 nM, respectively. The intra- and inter-day coefficient of variance was below 10% for all calibrator levels for both Zip and Smd-Zip. Validation of the sample handling procedure showed that samples are stable in room temperature or refrigerator for 3 days. Repeated freeze/thaw cycles, for five times did not affect the Zip or Smd-Zip concentration. In essence these findings state the importance of a correct sampling procedure for a functional ID M-procedure.

The TDM-procedure was applied on 10 patient serum samples obtained from a naturalistic clinical setting. The obtained concentrations, ranging from 66 to 432 nM for Zip and 42 to 220 nM for Smd-Zip were within the dynamic range of the present methodology. Thus, a future utility for this newly developed method in a TDM-setting seems evident.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84595 (URN)
Available from: 2012-10-15 Created: 2012-10-15 Last updated: 2012-10-15Bibliographically approved

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